Novel Association of Thymic Carcinoid with a Germline Mutation in a Kindred with Multiple Endocrine Neoplasia 1 (MEN1)

Abstract

Multiple endocrine neoplasia 1 (MEN1) is an autosomal dominant syndrome characterized by a triad of endocrine (parathyroid, enteropancreatic and pituitary) tumors. Familial MEN1 is defined by one first-degree relative having at least one of these 3 main tumors, and is associated with germline mutations in the MEN1 gene on 11q13 in a large proportion of cases. MEN1 patients may also develop non-endocrine tumors, notably thymic carcinoid. These are rare tumors found predominantly in men, and are a major cause of death in MEN1 due to their insidious nature, lack of effective treatment and unpredictable recurrence. Prophylactic thymectomy has been advocated for prevention but continued surveillance for recurrence is necessary. Although genotype-phenotype correlation in MEN1-related thymic carcinoid is inconsistent, there is a high prevalence of truncating mutations in this condition. We describe a father and son with MEN1, associated with thymic carcinoid (father) and the truncating mutation R29X (son), which was not previously reported in MEN1-related thymic carcinoid, and review the literature about thymic carcinoids in MEN1. Our cases illustrate the importance of a high index of suspicion for early diagnosis and lifelong surveillance in MEN1, and the utility of genetic analysis in defining surveillance for MEN1-related thymic carcinoid.

Key words

multiple endocrine neoplasia - cancer - hormones

• References

• 1 Bartsch D, Kopp I, Bergenfelz A et al. MEN1 gene mutations in 12 MEN1 families and their associated tumors. Eur J Endocrinol 1998; 139: 416-420
• 2 Boix E, Picó A, Pinedo R et al. Ectopic growth hormone-releasing hormone secretion by thymic carcinoid tumour. Clin Endocrinol (Oxf) 2002; 57: 131-134
• 3 Brandi ML, Gagel RF, Angeli A et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 2001; 86: 5658-5671
• 4 Burgess JR, Nord B, David R et al. Phenotype and phenocopy: the relationship between genotype and clinical phenotype in a single large family with multiple endocrine neoplasia type 1 (MEN 1). Clin Endocrinol (Oxf) 2000; 53: 205-211
• 5 Burgess JR, Giles N, Shepherd JJ. Malignant thymic carcinoid is not prevented by transcervical thymectomy in multiple endocrine neoplasia type 1. Clin Endocrinol (Oxf) 2001; 55: 689-693
• 6 Ferolla P, Falchetti A, Filosso P et al. Thymic neuroendocrine carcinoma (carcinoid) in multiple endocrine neoplasia type 1 syndrome: the Italian series. J Clin Endocrinol Metab 2005; 90: 2603-2609
• 7 Gibril F, Chen YJ, Schrump DS et al. Prospective study of thymic carcinoids in patients with multiple endocrine neoplasia type 1. J Clin Endocrinol Metab 2003; 88: 1066-1081
• 8 Goudet P, Murat A, Cardot-Bauters C et al. GTE network (Groupe des Tumeurs Endocrines). Thymic neuroendocrine tumors in multiple endocrine neoplasia type 1: a comparative study on 21 cases among a series of 761 MEN1 from the GTE (Groupe des Tumeurs Endocrines). World J Surg 2009; 33: 1197-1207
• 9 Gustincich S, Manfioletti G, Del Sal G et al. A fast method for high-quality genomic DNA extraction from whole human blood. Biotechniques 1991; 11: 298-300, 302
• 10 Karges W, Schaaf L, Dralle H et al. Concepts for screening and diagnostic follow-up in multiple endocrine neoplasia type 1 (MEN1). Exp Clin Endocrinol Diabetes 2000; 108: 334-340
• 11 Kouvaraki MA, Lee JE, Shapiro SE et al. Genotype-phenotype analysis in multiple endocrine neoplasia type 1. Arch Surg 2002; 137: 641-647
• 12 Lemos MC, Thakker RV. Multiple endocrine neoplasia type 1 (MEN1): analysis of 1336 mutations reported in the first decade following identification of the gene. Hum Mutat 2008; 29: 22-32
• 13 Lim LC, Tan MH, Eng C et al. Thymic carcinoid in multiple endocrine neoplasia 1: genotype-phenotype correlation and prevention. J Intern Med 2006; 259: 428-432
• 14 Matsubara S, Sato M, Ohye H et al. Detection of a novel nonsense mutation of the MEN1 gene in a familial multiple endocrine neoplasia type 1 patient and its screening in the family members. Endocr J 1998; 45: 653-657
• 15 Miller BS, Rusinko RY, Fowler L. Synchronous thymoma and thymic carcinoid in a woman with multiple endocrine neoplasia type 1: case report and review. Endocr Pract 2008; 14: 713-716
• 16 Paja Fano M, Goñi Goicoechea F, Yoldi Arrieta A et al. Type 1 multiple endocrine neoplasia associated to thymic carcinoid. Clinical and genetic study of one case. Med Clin (Barc) 2001; 116: 39
• 17 Sato M, Matsubara S, Miyauchi A et al. Identification of five novel germline mutations of the MEN1 gene in Japanese multiple endocrine neoplasia type 1 (MEN1) families. J Med Genet 1998; 35: 915-919
• 18 Schaaf L, Pickel J, Zinner K et al. Developing effective screening strategies in multiple endocrine neoplasia type 1 (MEN 1) on the basis of clinical and sequencing data of German patients with MEN 1. Exp Clin Endocrinol Diabetes 2007; 115: 509-517
• 19 Teh BT, McArdle J, Chan SP et al. Clinicopathologic studies of thymic carcinoids in multiple endocrine neoplasia type 1. Medicine (Baltimore) 1997; 76: 21-29
• 20 Teh BT, Zedenius J, Kytölä S et al. Thymic carcinoids in multiple endocrine neoplasia type 1. Ann Surg 1998; 228: 99-105
• 21 Teh BT, Kytölä S, Farnebo F et al. Mutation analysis of the MEN1 gene in multiple endocrine neoplasia type 1, familial acromegaly and familial isolated hyperparathyroidism. J Clin Endocrinol Metab 1998; 83: 2621-2626
• 22 The European Consortium on MEN1 . Identification of the multiple endocrine neoplasia type 1 (MEN1) gene. Hum Mol Genet 1997; 6: 1177-1183
• 23 Tso AW, Rong R, Lo CY et al. Multiple endocrine neoplasia type 1 (MEN1): genetic and clinical analysis in the Southern Chinese. Clin Endocrinol (Oxf) 2003; 59: 129-135